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Sweden deposited a sequence today from mid summer that carries indicators worthy of study.
Matches include the rare alternate coding for 225G found in the Norway3206-3 fatality sampled 6 weeks after the Swedish case and the NAsyn291V on that same Norwegian sample. Six weeks appear to be enough time for these changes to travel across borders. The HA sequences are identical, except for the 140S on Norway3206-3.
The two Scandinavian NA segments show a shared polymorphism at syn291V, a change that is found in 103 GenBank sequences including TamiFlu Resistant HK2369, Almati01, Tomsk01, Poland and with deep penetration through Italy and Catalonia. The NA segment of Norway3206-3 is identical to the Swedish NA.
Only this profiled private Swedish sequence from mid summer, CatNS2001 and CatNS2008 from early August and Norway3206-3 from September carry this variant Glycine coding at amino acid 225 that is seen as T717A, GGt->GGa. Neither of the cross segment pair, HAsyn413K or NAsyn407V, appears in the recent Scandinavian samples.
The Swedish sequence is a nucleotide match with Norway2674 and Norway2690 except for the RBD polymorphism 225E on the Norwegian sequences. Dialing back the resolution by 1 nucleotide, we find that the Swedish sequence is a 1724/1726 match with 2 more Norway 225E cases, Norway3059 and Norway4023. Delta is indicated after link to sequence.
If we return to the tighter resolution again, we find that the Swedish sequence is a exact nucleotide match except for the two nucleotides coding for 225D on 6 additional sequences from Sweden (1), Germany (1) and Russia (4). Delta is indicated after link to sequence.
This particular background is far from isolated. The homology between these 225D, 225E and 225G sequences raises a very basic question.
Does some mechanism in the protocol from sample to sequence potentially vary the outcome or block225Gmaterialisation on the resultant sequence? We know that lungs are being destroyed across extensive geography, yet few 225G sequences are being produced? Backing studies lead us to believe that 225G bearing samples will grow well in a receptor environment rich in α2-3-linked sialic acid.
MDCK cell lines specialised to overexpress α2-6-linked sialic acid at the expense of α2-3-linkedSA are being employed in Neuraminadase Inhibitor sensitivity testing, demonstrating that these canine cell lines are adaptable in linkedSA expression. Exactly how sensitive is the culture environment that is being used as a predecessor to sequencing? How consistent are the protocols and materials between labs?
Does a possibility exist that current MDCK cell lines being used are underexpressing α2-3-linked sialic acid in a manner consistent with the low numbers of resultant 225G sequences that have been published? Are samples that are originating with225G not growing well due to a limited ratio of matched receptors? We specifically enquire here on the cell lines, but obviously all aspects of the growth environment must be inspected for inhibitors to225Gmaterialisation if the presenting sample sequences are to be accurately elicited.
Similar rare codings for Glycine at residue 225 occurring in temporal sequence from Sweden in late summer, to Catalonia in early August, and onward to Norway on September 1<sup>st</sup> beg for any explanation other than "spontaneous" mutation within a pandemic reservoir, ΣPF11, that is actively demonstrating an ability to share data.
Is 225G transmitting? Is 225G transmitting in 2 variant forms? Is 225G now confirmed as Hydra?
Thank you NS1. So basically we could have a very wide spread phenomena of 225G. Is 225G the only marker for virulence that might explain the severe pneumonia in H1N1?
Re: 225G Preliminary Worldwide Tracking & Evaluation
Gs,
Thank you for posting the entire GenBank panflu sequences and their mutations. I cannot imagine the hours that went into making that file.
Most mutations seem to be shown in their amino acid form, such as D225G = ?716 or H247Y = ?; is there some easy way to look at the nucleotide mutations and know what they are on the amino acid level?
The salvage of human life ought to be placed above barter and exchange ~ Louis Harris, 1918
blastm should hopefully work for this too,
but it doesn't distinguish mutations, so it prints all sequences
with 225G(H3) and 225E(H3) when you type
blastm mexfluae.mp1 239 4
(H3-numbering+14=H1-numbering)
I might change that ... but usually we want all the mutations
at a position, and sometimes there are mixed signals
(my protein program can't handle that - another change to do...)
(this is also only reading frame 0, so proteins M2,NS2,PB1-F2
are not decoded)
Thank you NS1. So basically we could have a very wide spread phenomena of 225G. Is 225G the only marker for virulence that might explain the severe pneumonia in H1N1?
from NS1 -
You?ll get the odd feeling that we are providing you a non-answer by the end of this reading and you?ll be correct. You don?t have to read between the lines to see that when the data collection, that is already sparse and disconnected, comes into question at the basic level, we all have to rebalance our variables.
Based on what we?ve just seen with the coincident 225D, 225E and 225G on the same backgrounds, our estimation and questions on the lab protocol need answers before we can make any inroads with accuracy. If the 225G is not being detected properly due to receptor specificity on the cell lines, incubation temperature or nutrient mix, then other important Avian polymorphisms are also undetected. The situation begins to fall into the hilarious, but dangerous, category of ?we don?t know what we don?t know?.
That?s why we described the ?process? of Influenza Flux, an ebb and flow of inter-species data falling onto a melded platform, being tested and either becoming fixed or reverting. We are certainly in a dangerous period and that period will continue for quite some time. Even if this reservoir holds at the present position, the toll is going to be significant as multiplicity of exposure cycles through major areas in the winter. We propose a less than 10% probability that this reservoir is peaking in trait enhancing acquisitions now or during the next 30 days.
Now that we see the testing anomaly that may be endemic to industry, our model becomes more important to us in the next 30 days as a framework and less important at the detail level. We?ll investigate the micro trends and weight the outcomes based on potential for missed Avian changes and then restructure the heuristics based on those findings hoping that testing revises.
If pandemic influenza weren?t dangerous enough, now we have to deal with unfocused microscopes as a norm.
The HA and NAcross segmentpairing of silent polymorphisms noted on the four fatal 225G cases from the Ukraine has now been tracked to 29 sequences around the globe on a cumulative study showing a quantifiable density in Spain.
HA:syn413K encoded from A1281G, AAa->AAg*
NA:syn407V encoded from T1221C, GTt->GTc*
* SNP Matches the 4 fatal flashfire cases
The most recent public database entries at GenBank are from Spain and were sampled in November 2009.
The depth of this background continues to increase with 2 TamiFlu Resistant strains reported in 2 days. The persistance of this cross segment correlation may signal a viral genetic acquisition response to widespread TamiFlu usage. These silent polymorphisms are suggestive of an intermediate stage that is moving in the direction of antiviral resistance and continued Receptor Binding Domain revisions due to antiviral blanketing.
Reassortment, which is the rearrangement of viral gene segments in a host cell infected with two different viruses, is an important mechanism for the evolution of influenza viruses. Mixed infections with multiple virus types could lead to reassortment. To better understand the occurrence of quasispe …
We describe a new approach to comprehensively identify mixed infections and quasispecies in low passage influenza A isolates and cloacal swabs and add to the understanding of the ecology of influenza A virus populations.
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